EGFR (Epidermal Growth Factor Receptor), also known as HER1 or ErbB1, is a receptor for cell proliferation and signal transduction of the epithelial growth factor (EGF). EGFR belongs to a member of the ErbB receptor family which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). EGFR is a transmembrane glycoprotein with a molecular weight of 170 KDa, which belongs to a tyrosine kinase receptor.
EGFR is located on the surface of cell membranes and is activated by binding to ligands including EGF and TGFα. Upon being activated, EGFR undergoes a transition from a monomer to a dimer. The dimer includes not only the binding of two identical receptor molecules (homodimerization) but also the binding of different members of the human EGF-associated receptor (HER) tyrosine kinase family (heterodimerization). EGFR can activate its intracellular kinase pathways after dimerization, resulting in the phosphorylation of key tyrosine residues in the intracellular domain and the stimulation to many intracellular signaling pathways involved in cell proliferation and survival.
There exist high or abnormal expressions of EGFR in many solid tumors. EGFR is associated with tumor cell proliferation, angiogenesis, tumor invasion, metastasis and the inhibition of apoptosis. Possible mechanisms include the followings: enhanced downstream signal transduction caused by the high expressions of EGFR; the sustained activation of EGFR caused by the increased expressions of mutant EGFR receptors or ligands; the enhanced effect of autocrine loops; the destruction of receptor downregulation mechanisms; and the activation of aberrant signaling pathways, etc. Overexpressions of EGFR play an important role in the progression of malignant tumors. For example, overexpressions of EGFR have been found in gliocyte, kidney cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and other tissues.
Aberrant expressions of EGFR and Erb-B2 play a crucial role in tumor transformation and growth. In the case of lung cancer, EGFR is expressed in 50% of non-small cell lung cancer (NSCLC) cases and its expression is associated with poor prognosis. The two factors allow EGFR and its family members to be major candidates of targeted therapy. Two types of small molecule inhibitors targeted to EGFR, gefitinib and erlotinib, were rapidly approved by the FDA of USA for the treatment of advanced NSCLC patients who have no response to traditional chemotherapy.
Early clinical data indicated that 10% of NSCLC patients have response to getifinib and erlotinib. Molecular biological analysis shows that in most cases, drug-responsive patients carry specific mutations in the EGFR-encoding genes: the deletion of amino acids at positions 747-750 in exon 19 accounts for 45% of mutations, and 10% of mutations occur in exons 18 and 20. The most common EGFR-activating mutations (L858R and delE746_A750) result in an increase in affinity for small molecule tyrosine kinase inhibitors (TKI) and a decrease in affinity for adenosine triphosphate (ATP) relative to wild type (WT) EGFR. T790M mutation is a point mutation in exon 20 of EGFR, which leads to acquired resistance to the treatment with gefitinib or erlotinib. A recent study shows that the combination of L858R and T790M mutations has a stronger affinity for ATP than L858R alone, and TKIs are ATP-competitive kinase inhibitors, and thereby resulting in a decreased binding rate between TKIs and kinase domains.